1. Dr. Zahra Hesari Pharm D, PhD of Pharmaceutics
Pre-formulation
Dr. Zahra Hesari
Pharm D, PhD of Pharmaceutics
Session 3
Guilan university of Medical Sciences, Faculty of Pharmacy

2. Review potency Proteins Solid dosage form excipients Organic Salts
(Dose)
Hydrates & solvates
Organic esters
LogP
pKa
Membrane permeability

3. Drug and Drug Product Stability
Drug samples of known purity
Stability studies in the preformulation phase:
Solid-state stability of the drug alone
Solution-phase stability
Stability in the presence of expected excipients
Initial investigation: drug’s chemical structure
Drug substances (Chemically):
alcohols, phenols, aldehydes, ketones, esters, ethers, acids, salts, alkaloids, glycosides

4. Drug Stability Mechanisms of Degradation
Most frequently chemical destructive processes
Hydrolysis
Oxidation
Drug molecules interact with water molecules to yield breakdown products
Great number of drugs are esters or contain such other groupings as substituted amides, lactones, and lactams
Aldehydes, alcohols, phenols, sugars, alkaloids, and unsaturated fats and oils
Loss of electron, increase in the positive valence, loss of hydrogen
Free chemical radicals
Autoxidations: (atmospheric oxygen- chain reaction)

5. Kinetics and Shelf Life
Stability definition
Stability concern types:
Chemical
Physical
Microbiologic
Therapeutic
Toxicologic
Chemical stability
Storage conditions
Proper container
Anticipating interactions when mixing drugs and dosage forms
Stability and expiration dating are based on reaction kinetics

6. Reaction kinetic Expiration dating Stability
Study of rate of chemical change
This rate is influenced by concentration of reactants, products and solvent, pressure and temperature.

7. Rate Reactions
Reaction rate is a description of the drug concentration with respect to time.
Most commonly in pharmacy
Zero-order reaction
First-order reactions

8. Q10 Method of Shelf Life Estimation
Estimate shelf life for a product that has been stored or is going to be stored under a different set of conditions

9. Enhancing Stability of Drug Products
Incorporation of excipients
Increase the stability of the drug substance
Hydrolysis:
Hydrolysis & Oxidation
reduction or elimination of water:
waterproof protective coating over tablets
keeping the drug in a tightly closed container
substitute liquids such as glycerin, propylene glycol, and alcohol
Anhydrous vegetable oil in injectable products
Suspending in a nonaqueous vehicle rather than dissolving in an aqueous solvent
Dry form for reconstitution (sp antibiotics)
Refrigeration
pH (5-6), buffering agents

10. Enhancing Stability of Drug Products
Oxidation
Humidity in presence of oxygen or light
Combination with other chemicals
Alteration in the color, precipitation or a change in odor
Antioxidants: providing electrons and hydrogen atoms
Aqueous preparations:
sodium sulfite (Na2SO3, at high pH)
sodium bisulfite (NaHSO3, at intermediate pH)
sodium metabisulfite (Na2S2O5, at low pH)
hypophosphorous acid (H3PO2)
ascorbic acid
Oleaginous (oily or unctuous)
Preparations:
alpha-tocopherol,
Butyl hydroxy anisole
ascorbyl palmitate

11. No generally suitable substitutes for sulfites
Preservative
Injectable drugs, such as antibiotics and local anesthetics
inhalants and ophthalmic preparations
few oral drugs
FDA labeling regulations
0.2% of the population who are subject to allergic reactions
Food products
Antioxidant + other pharmaceutical additives
Antioxidant + drug substance
oxygen-free atmosphere during preparation and storage
No generally suitable substitutes for sulfites
potassium bisulfite, potassium metabisulfite, sodium bisulfite, sodium metabisulfite, sodium sulfite, and sulfur dioxide.

12. Oxidation Trace metals Light (catalyst) Temperature pH
Purification of the source
Chelating agents: calcium disodium edetate and EDTA
Light (catalyst)
packaging in light-resistant or opaque containers
Temperature
Keep in cool place pH
Most favorable for each
preparation
Potassium Iodide Oral Solution, USP
Yellow to-brown discoloration
light-resistant containers
addition of 0.5 mg of sodium thiosulfate for each gram of KI.

13. Formulation pharmacist may stabilize the preparation by the selective exclusion from the system of oxygen, oxidizing agents, trace metals, light, heat, and other chemical catalysts to the oxidation process. Antioxidants, chelating agents, and buffering agents may be added to create and maintain a favorable pH.
Other less frequent destructive processes include polymerization, chemical decarboxylation, and deamination.

14. Drug-Excipient Compatibility
Stress condition
Guideline of accelerated stability studies
Temp, pH, light, moisture, agitation, gravity, packaging, method of manufacture
Experimental studies:
Mixing drug with excipients
Aqueous suspension of Drug-Excipients
Factorial design
water addition: yes/no,
Temp: 25 or 40 ‘C
Time: 1 or 4 week
High temp & high humidity
Intact drug & degradation product are measured
Drug content, color, taste, related substances

15. Advanced analytical instrumentation
Detect low levels of degradation products (less than 2%)
Thermal analysis (DTA, DSC)
Chromatographic methods (HPLC, LC/MS)
Diffuse reflectance spectroscopy (DRS)

16. Stability Testing Pharmaceutical components and finished products
FDA’s GMP and ICH guideline:
“Stability Testing of New Drug Substances and Products”
“Quality of Biotechnological Products: Stability Testing of Biotechnology/Biological Drug Products”
“Photostability Testing of New Drug Substances and Products”
“Stability Testing of New Dosage Forms”
Drug stability is important during preclinical testing and in clinical (human) trials
For marketed drug product is vital during shelf life

17. Stability assessment before approval for marketing:
Influence of pharmaceutical ingredients
Influence of the container and closure
The manufacturing and processing conditions (e.g., heat)
Packaging components
Conditions of storage
Anticipated conditions of shipping, temperature, light, and humidity
Anticipated duration and conditions of pharmacy shelf life and patient use.
In-process stability testing
Packaging features

18. Extemporaneous compounded formulations
USP guidelines on stability:
nonaqueous liquids and solid formulations in which the manufactured drug is the source of the active ingredient, not later than 25% of the time remaining until the product’s expiration date or 6 months, whichever is earlier.
nonaqueous liquids and solid formulations in which a USP or National Formulary (NF) substance is the source of active ingredient, a beyond-use date of 6 months.
watercontaining formulations prepared from ingredients in solid form, a beyond-use date not later than 14 days in storage at cold temperatures.
all other formulations, a beyond-use date of the intended duration of therapy or 30 days, whichever is earlier.

19. Thank You !
Handout